15-dehydro-16 methyl steroids and process for the production thereof



United States Patent 3,219,674 -DEHYDRO-16 METHYL STEROIDS AND PROC- ESSFOR THE PRODUCTION THEREOF Octavio Mancera, Howard J. Ringold, and CarlDjerassi,

all of Mexico City, Mexico, assignors, by mesne assignments, to SyntexCorporation, a corporation of Panama No Drawing. Filed Feb. 24, 1960,Ser. No. 10,553 Claims priority, application Mexico, Mar. 11, 1959,53,927; May 6, 1959, 54,480 22 Claims. (Cl. 260397.4)

The present invention relates to a new process for the production ofcertain cyclopentanophenanthrene derivatives.

More particularly, it relates to the production of 160:-methyl-17a-hydroxy-20-keto-pregnanes, which compounds are valuableintermediates in the manufacture of the important steroidal16cz-methyl-hormones by methods which have been described in theliterature.

The hitherto used processes for preparing the16amethyl-l7u-hydroXy-20-keto-pregnanes involve the hydroxylation of aIGa-methyl-ZO-keto compound at C-17a by the method of Gallagher. Thiswell known method comprises the formation of the -eno1 acetate, thesubsequent epoxidation of the double bond between C-l7 and C-20 of theenolized compound by treatment with a peracid, and finally an alkalinetreatment in order to obtain the 17 x-hydroxy-20-keto compound; however,in the presence of a methyl group at C-16 and also in the presence ofdouble bonds at C-9, 11 and/or at (3-5, 6, which are susceptible tooxidation by the peracid, this method suffers from the drawback ofrendering only unsatisfactory yields.

We have now made the surprising discovery that the easily accessible16fl-methyl-l6oz,l7a-oXido-20-keto-pregnames can be converted to therespective 16oc-methyl-l7uhydroxy-20-keto-pregnanes by the novel processaccording to the invention, which comprises, as an essential feature,the process steps illustrated by the following reaction sequence:

CH R (FHQR CH R CO ('30 ICO .W CH3 "CH3 (II) (III) wherein R is a memberof the group consisting of hydrogen, the hydroxyl group, and theacyloxyl radical of a hydrocarbon carboxylic acid having up to 12 carbonatoms and being saturated or unsaturated, of straight or branched chain,cyclic or mixed cyclic aliphatic, unsubstituted or substituted withmethoXy, halogen or other groups.

This process for producing l6a-methyl-l7a-hydroxy- ZO-keto-pregnanesaccording to the invention thus comprises reacting a16,8-rnethyl-16a,17a-oxido-20-keto pregnane derivative (I) with ahydrogen halide in an inert organic solvent so as to obtain thecorresponding 16- methyl-A -17oz-hydroxy-ZO-keto-pregnane derivative(II), and reacting the latter with hydrogen in thepresence of ahydrogenation catalyst so as to obtain the corresponding 16:! methyl17cc hydroxy ZO-keto-pregnane derivative (Ill).

The term hydrogen halide refers to preferably the saturated aqueoussolutions thereof, for instance hydrochloric acid having a concentrationof from 33 to 37% by weight HCl.

The hydrogen halide can also be applied in the form of a tertiary aminehydrohalide, whereby the hydrogen halide is set free in situ from thecomplex organic salt during the reaction.

Although in general the reaction of methyl-16a, 17a-oxido-compound witha hydrogen halide gives rise to the formation of halohydrine, we havediscovered that under the conditions outlined in more detail furtherbelow, this reaction leads to the unsaturated 16-methyl- A -compoundrepresented by Formula II.

We prefer to treat the starting compound with concentrated hydrochloricor hydrobromic acid in certain oxygen containing organic solvents amongwhich there are acetone, methyl-ethyl ketone, dioxane and similarcompounds at a temperature in the range from below -10 C. to roomtemperature. The preferred solvent is acetone and the preferredtemperature range 0 to 10 C.

When using the hydrohalide of a tertiary amine such as pyridinehydrobromide, pyridine hydrochloride, collidine hydrobromide, collidinehydrochloride, or the like, the above treatment of the starting compoundis carried out in a lower aliphatic alcohol such as ethanol or methanolas the solvent, and at a temperature ranging from room temperature tothe reflux temperature.

We assume that during the above described treatment with hydrogenbromide, there is formed an intermediate l6-methyl-16,17-bromohydrinwhich spontaneously dehydrobrominates to give the unsaturated Compound11.

The intermediate II is in turn hydrogenated to Compound III, preferablyin an alcoholic solution, for instance in methanol, and in the presenceof apalladium on charcoal catalyst.

The fact that the hydrogenation proceeds from the same side of thesteric configuration of the angular methyl group at C-lO, that is, fromthe fl-side, and-thus gives rise to the methyl group at C-16 in therat-position, is another surprising feature in the process according toour invention. For it was to be expected that the hydrogenation wouldtake place from the a side resulting in the formation of the l6j8-methylcompound. It is further noteworthy that the hydrogenation does not causethe loss of the 17a-hydroxyl group in spite of the fact that this groupis activated by the proximity of the keto group at C-20 and by being anallylic hydroxyl group.

The hydrogenation of intermediate II to Compound III is also effected inthe presence of a nickel catalyst and the methanol solvent in thehydrogenation step may be replaced by another solvent, such as ethylacetate, but always the hydrogenation is interrupted after the uptake of1 molar equivalent of hydrogen.

The starting compound for the process according to the invention isselected from the group consisting of the compounds of the generalformulas:

wherein R is selected from the group consisting of hydrogen, hydroxy andacyloxy; X is selected from the group consisting of hydrogen andfluorine; Y is selected from the group consisting of :0, OL-hYdI'OXY,B-hydroxy, ocacyloxy and fi-acyloxy; Y is selected from the groupconsisting of :0, a-hydroxy, B-hydroxy and a-acyloxy; when Y is :0, Z isselected from the group consisting of a single bond between C5 and C6with the hydrogen attached to C5 in tat-position and such single bondbetween 06 and C6 with the hydrogen attached to C5 in fi-position; whenY represents a member of the above described group other than =0, Z isselected from the group consisting of a double bond between C-5 and C6,a single bond between C5 and C6 with the hydrogen attached to C5 inu-position, and a single bond between C5 and C6 with the hydrogenattached to C5 in the fl-position; the aforesaid acyloxy and acyl groupsbeing those of a hydrocarbon carboxylic acid having up to 12 carbonatoms.

Those of the above mentioned starting compounds having a free oresterified 3fi-hydroxyl group can be obtained from A -20-keto-pregnanesof the formulas CHzR do li i wherein R, X, and Y have the same meaningas defined above; R is selected from the group consisting of hydrogenand acyl; Z is selected from the group consisting of a double bondbetween -5 and C6 and a saturated linkage between C and C6 with thehydrogen atom at C5 in aor fi-position. The introduction of the 16,8-methyl group and of the l6a,l7a-oxido group is efiected by reacting theabove compounds in a known manner with diazomethane to obtain thecorresponding pyrazoline and decomposing the latter by means of thethermal treatment described by Wettstein in Helv. Chim. Acta, XXVII,1803 (1944) to produce the corresponding 16-methyl-A -keto pregnanederivative, and then reacting the latter, for instance, with alkalinehydrogen peroxide so as to obtain the corresponding16,8-methyl-l6a,17a-oxido-20- keto pregnane derivative. Since thislatter reaction is accompanied by the hydrolysis of ester groups, whichmay be present at C3 (R acyl), the resulting 3-hydroxy group has to bere-esterified, if desired, by conventional methods. In a specific modeof carrying out the invention, the 3B-hydroxyl group of the compoundshaving a single bond between C5 and C6 is further oxidized to the 3-ketogroup in the conventional manner with chromic acid to obtain startingmaterials wherein Y equals :0.

The above described conventional reactions leading to the startingmaterial (I) can be carried out at very high yield rates, and the yieldrates of the steps comprised in the process according to the inventionare equally in the order of and higher.

In contrast thereto the conversion of a A compound to the corresponding16x-methyl-l7a-hydroxy-compound via a Grignard reaction for introducingthe methyl group at C16 and the Gallagher reaction for introducing thehydroxyl group at C17oc proceeds with only low overall yields.

Another suitable starting material for the process according to theinvention is 91x fluoro l6 methyl 16a, 17a oxido pregnan 11,8 ol 3,20dione, which was obtained, for instance, from A-pregnen-3a-ol-11,20-dione, described by Slates et al. in J. Org. Chem,22, 499 (1957), by the following reaction sequence: the keto group at0-20 was protected by formation of the cycloethyleneketal; the ll-ketogroup was then reduced to the p-hydroxyl group by reaction with lithiumaluminium hydride; upon hydrolysis of the ketal group there was obtainedA -pregnene-3a,1lfl-diol-ZO-one; by reaction with diazomethane followedby pyrolysis of the resulting pyrazoline there was obtained 16-methyl-A-pregnene-3(1,1 1B- diol-20-one; after acetylation at C3, the lattercompound Was dehydrated by reaction with methanesulfonyl chloride indimethylformamide-pyridine to form the acetate of 16- methyl-A-pregnadien-3a-ol-20-one. The acetoxy group was hydrolyzed and thenoxidized to l6-methyl- A -pregnadiene-3,20-dione. There was then appliedthe method of Fried et al. for introducing a halogen atom at C9a asdescribed in J. Am. Chem. Soc., 79, 1130 (1957), and thus there wasobtained 16-methyl-9u-fluoro- A -pregnen-11,8-ol-3,20-dione. Its doublebond at 0-16, 17 was epoxidized by reaction with hydrogen peroxide inalkaline conditions and the resulting 16,8-methyl-9a-fluoro-16a,l7a-oxido-pregnan-1lfi-ol-3,20-dione (I) was then submitted to theprocess of the present invention.

Depending on which of the above-described starting materials have beenused there are obtained the aforesaid end products (III) of thefollowing formulas:

@W Y Z CHZR (1) Cr-Os (2) HCl/AeO H (III) to i Ringold Stork- Iodinationarm (:30

1cm omooor:

omococm do ----0H you;

dehydrogenation 0- (VI) Z2 omoooom o TAUREH. I i O\/ iIVII) This processcomprises the steps of oxidizing the 3-hydroxy group of Compounds 111 tothe 3-keto-group as in Compounds IV, for instance, with chromiumtrioxide, then a conventional treatment with an acid or base to shift aneventually present A -double bond to A introducing iodine at C-21, forinstance, by the method of Ringold- Stork supra; acetolysis of the21-iodo Compounds V to obtain the lu-methyl derivatives (VI) of, forinstance,

cortisone or cortexolone (Reichsteins Substance S). Conventionaldehydrogenation of the latter with selenium dioxide, or of thecorresponding allopregnane derivative (VI, in which Z represents asingle bond) via the 2,4-dibromo intermediate yields the A -CompoundsVII such as, for instance, l6a-methyl-prednisone.

The invention is further illustrated but not limited by the followingexamples:

Example 1 20 cc. of aqueous hydrobromic acid solution of constantboiling point was slowly added to a stirred solution of 5 g. of-methyl-16a,17a-oxido-allopregnan-35-01-11, 20-dione in 100 cc. of pureacetone, maintaining the temperature around 10 C. The mixture wasstirred for half an hour more at 10 C., diluted with ice water and theprecipitate was collected by filtration, dried and recrystallized fromacetone-hexane. There was thus obtained 16- methyl A allopregnene3fl,17oc-di0l 11,20 dione; M.P. 258259 C.; [uJ -64.3 (pyridine).

The above compound was hydrogenated in 400 cc. of methanol, in thepersence of a prereduced 5% palladium on charcoal catalyst, at roomtemperature, until the equivalent of 1 mol of hydrogen had beenabsorbed, which took a few minutes. The catalyst was removed byfiltration, the filtrate was evaporated to dryness under reducedpressure and the residue was purified by chromatography on neutralalumina. There was thus obtainedlfiot-methylallopregnane-3B,17or-diol-11,20-dione; M.P. 254-255 C. [ab+220 (pyridine).

The starting material, namely lliamethyl-lfilh-oxidoallopregnan-3fi-ol-11,20-dione was prepared in the followingmanner:

A solution of 7 g. of the acetate of A -allopregnen-3 B- ol-11,20-dione,described by Djerassi et al. in J. Am. Chem. Soc., 74, 3634 (1952), in200 cc. of an ether solution of diazomethane, prepared from 50 g. ofnitrosomethyl urea, was kept at room temperature for 24 hours; 5 cc. ofacetic acid was then added, the solvent was evaporated under reducedpressure and at room temperature, almost to dryness, and the residue wascrystallized from acetone to give the 3-acetoxy-pyrazoline which wasdecomposed by means of the thermal treatment described by Wettstein(Halv. Chim. Acta, XXVII, 1803 (1944)), by gradually heating to about180 C. under vacuum. Recrystallization of the crude product fromacetone-hexane yielded the acetate of 16-methyl-A -allopregnen-3,8-ol-11,20-dione; M.P. 165-166 C.; [aJ +25.9 (chloroform); 248-250 m310-314 m log 5 3.98 and 2.09.

A solution of 5 g. of the above last mentioned compound in 350 cc. ofmethanol was treated with 20 cc. of a 4 N aqueous solution of sodiumhydroxide and immediately afterwards with 20 cc. of 30% hydrogenperoxide, with stirring and maintaining the temperature around 15 C. Themixture was kept overnight in the refrigerator, poured into ice waterand the precipitate was collected by filtration, washed with water anddried. Crystallization from acetone-hexane afforded the pure16,8-methyl-16a, 17a-oxido-allopregnan-3/3-ol-11,20-dione; M.P. -186;[0:1 +87.3 (chloroform).

Example 2 In accordance with the preceding example, the reaction of165-methyl-16a,17a-oxido-allopregnan-3B-ol-11,20-dione acetate preparedby acetylation of the free oxide in a conventional manner, withhydrobromic acid .alforded the acetate of 16-methyl-A-allopregnene-3p,17x-diol-11,20- dione. The latter was hydrogenated asdescribed in such example, to form the 3-acetate of16a-methyl-allopregnane-3fi,l7a-diol-11,20-dione. By subsequenttreatment with 1% potassium hydroxide at room temperature and under anatmosphere of nitrogen there was obtained 16amethyl allopregnane 38,170; diol 11,20 dione, identical with the final compound of thepreceding example.

Example 3 In accordance with the method described in Example 1, 165methyl 16a,17,a-oxido A5901) pregnadien 3% ol-20-one was converted into16-methyl-A -pregnatriene-3,8,17a-diol-20-one and then by hydrogenationof the latter there was obtained 1Ga-methyl-A -pregnadiene-3 B, l7a-diol-20-one.

The starting material, 16cc,17oc-0Xid0-A -pregnadien-3B-ol-20-one wasobtained by dehydration of A pregnadiene-3B-11a-diol-20-one, describedby O. Halpern et al. in J. Am. Chem. Soc., 81, 439 (1959), using themethod described by G. Rosenkranz et al. in J. Am. Chem. Soc., 76, 2228(1954), followed by epoxidation of the 16,17 double bond, in accordancewith the method of Example 1.

Example 4 By substituting in the method of the preceding example the16,8-methyl-16a,17a-oxido-A -pregnadien-Sfi-ol- 20-one by its acetatethere was obtained upon reaction with hydrobromic acid the 3-acetate of16-methyl-A pregnatriene-36,17a-diol-20-one. Hydrogenation of the latterattorded the 3-acetate of 16a-methyl-A -pregnadiene-3[3,17oc-CliOl-20-OI15, and finally by alkaline hydrolysis, in accordancewith the method of Example 2, there was obtained l6a-methyl-A-pregnadiene-35,17a-diol- 20-0ne,

In accordance with the method of preparation described in Example 1, thecompounds listed below under I were converted into the corresponding16,6-methyl-16a,17a-oxides, which by treatment with hydrobromic acid inacetone solution, followed by hydrogenation, by the method describedalso in Example 1, afforded the corresponding 16ccmethyl-17a-hydroxycompounds listed under III via the A -intermediate listed under H.

Example I II 5 A -allopregnen-3B-ol-2O-one. lfi-methyl- A -allopregnene-Known and conventional. 35, 17a-di01-20-0ne.

III 16 a-methyl-allopregnane- 3fl,17adiol-20-one.

I II 6 A -pregnen-3a-ol-1L20- 16-methyl-A -pregnene 20-dione acetate.Rosen- 3a,17a-diol-11,20-dione. kranz et al., J. Am. Chem. Soc., 75,4431 (1953).

III l6a-methyl-pregnane-3a, 17 a-dil-11,20-dione.

I II 7 A -all0pregnadien-3fllfi-methyl- A -alloo1-20-one 3-acetate.Djerpregnadiene-3fi,l7a-diolassi et al., J. Org. Chem. 20-0ne. 16, 1278(1951).

III lfia-methyl- A -alloprcg- Dene-319, 17 a-di0l-20-0ne.

I II 8 A -pregnadiene-3fl,11alfi-methyl- N -pregnadiol-20-one. O.Halpern diene-Bfl,11a,17a-triol-20- et al., J. Am. Chem. Soc. one. 81,439 (1959).

III lfia-methyl- A -pregnene- 35,1111, 17a-triol-20-one.

Example 9 A stirred solution of 2 g. of the acetate of 16,6-methyl-16a,l7et-oxido-A -pregnen-3 3-ol2O-one in 160' cc. of acetone wastreated with 8 cc. of an aqueous hydrobromic acid solution of constantboiling point, maintaining the temperature around 5 C. After minutes thereaction mixture was poured into ice water, the precipitate collected byfiltration, dried and recrystallized from acetonehexane; there was thusobtained the acetate of 16-methyl- A -pregnadiene-3B,17a-diol-20-one;M.P. 209-211 C.;

[041 154.2 (chloroform) in 90% yield.

The above compound was hydrogenated in accordance with the method ofExample 1, to 'afiiord 16a-methyl-A pregnene-B/S,17a-diol-20-one Ii-acetate; M.P. 202-204; [oc] '67 (chloroform).

The starting material 16B-methyl-16a,17x-oxido-A pregnen-3,B-ol-20.-one3-acetate was obtained from 16 8- methyl-A -pregnadien-3B-ol-ZO-one3-acetate described by Wettstein et al. in Helv. Chim. Acta, XXVII, 1603(1944), by the epoxidation method described in EX ample 1.

Example 10 A solution of 12 g. of 16,8-methyl-l6a,l7u-oxido-Apregnen-3/3-ol-20-one obtained by epoxidation of 16pmethyl-A-pregnadiene-3,8-ol-20-one described by Wettstein et al. in Helv. Chim.Acta, XXVII, 1803 (1944), in 360 cc. of acetone was treated with 35 cc.of concentrated hydrochloric acid (35.5%), maintaining the temperaturearound 5 C., a precipitate separated almost immediately after theaddition of the acid. The mixture was stirred for 30 minutes more at 5C., the precipitate collected and washed with acetone-Water 1:1. Therewas thus obtained 16-methyl-A -pregnadiene-3B,17a-diol-20-one in yield,M.P. 235-245; after several recrystallizations from acetone-hexane theMP. was raised to 263-268 C.

Example 11 In accordance with the method of the previous example,16B-methyl-16a,17a-oxido-allopregnan 31,8 ol-11,20-dione was treatedwith concentrated hydrochloric acid, but methyl ethyl ketone was used assolvent, instead of acetone; there was obtained 1g6-methyl-A-allopregnene-3B, 170c-(ll0l-11,20dl0116, identical with that obtainedin EX- ample 1.

Example 12 A solution of 1 g. of 16p-methyl-16a,17a-0xido-Apregnen-3fi-ol-20-one in 25 cc. of dioxane was treated with 0.25 cc. ofconcentrated hydrochloric acid and the reaction mixture heated on thesteam bath for 20 minutes. It was then poured into ice-water, extractedwith methylene chloride, the organic layer washed with 5% sodiumcarbonate solution and water to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness. Chromatography of the crude producton neutral alumina gave '16-methyl-A -pregnadiene-3B,17a-diol-20-one in15-20% yield.

Example 13 A mixture of 3 g. of the acetate of16}8-methyl-16u,17aoxido-A -pregnen-3,8-ol-20-one, cc. of absoluteethanol and 3 g. of pyridine hydrochloride was refluxed for 3 hours,concentrated under vacuum almost to dryness and the residue was dilutedwith ice water. The precipitate was collected, washed with water, driedand crystallized from methanol. There was thus obtained the 3- acetateof 16-methyl-A -pregnadiene-3B,17a-diol-20-one, identical with theproduct obtained in Example 9.

Example 14 Example 13 was repeated but using collidine Ihydrobromide.There was also obtained the 3-acetate of 1.6- methyl-A-pregnadiene-3B,17a-diol-2O-0ne.

Example 15 A solution of 1 g. of the acetate of16,8-methyl-16a,17aoxido-allopregnan-3fi-ol-l1,20-dione in 50 cc. ofabsolute methanol was treated with 1 g. of pyridine hydrochloride andthe reaction mixture kept at room temperature for 96 hours. It was thenconcentrated under vacuum to a small volume, poured into ice water andthe precipitate was filtered and recrystallized from acetone-hexane,thus alfording the acetate of 16-methyl-A -allopregnene-3{3,17a-diol-11,20-dione, identical with that obtained in Example 2.

9 Example 16 A solution of 1 g. of16,6-methyl-16a,17zx-oxido-allopregnan-3 8-ol-11,20-dione-acetate in 20cc. of acetone was treated with 5 cc. of a 57% aqueous solution ofhydroiodic acid and the mixture allowed to stand at room temperature for30 minutes, diluted with ice water and the precipitate collected byfiltration. Recrystallization from acetonehexane gave l 6a-methyl-n-pregnen-35,17a-diol-11,20-dione 3-acetate.

The above compound was hydrogenated as described in Example 1, affording16a-methyl-allopregnan-3fi,17adiol-11,20-dione-acetate identical to thatobtained in Example 2.

Example 17 A solution of 5 g. of16a-methylallopregnane-3B,17adiol-ll,20-dione, obtained as described inExample 1, in 500 cc. of acetone was cooled to C., flushed with nitrogenand slowly treated under stirring with an 8 N solution of chromic acidprepared in dilute sulfuric acid, until the brown-red color of chromiumtrioxide persisted in the mixture. It was then kept at 0 C. for 10minutes further, then diluted with ice water and the precipitate wascollected by filtration, washed with water, dried and recrystallizedfrom acetonehexane, thus furnishing 16amethyl-allopregnan-17a-ol-3,1 1,20-trione.

A cooled solution of 4 g. of the above compound in 30 cc. oftetrahydrofurane and 18 cc. of methanol was treated with vigorousstirring with 6 g. of calcium oxide and then with 6 g. of iodine. Themixture was stirred at room temperature until the color of the solutionturned pale yellow, then poured into ice water containing 16 cc. ofacetic acid and 2 g. of sodium thiosulfate and stirred for 15 minutes;most of the liquid was decanted and the precipitate was collected byfiltration, washed with water and dried under vacuum. There was thusobtained the crude 16a-methyl-21-iodo-allopregnan-1704-01-3 ,11,20-trione.

The above substance was mixed with 100 cc. of anhydrous acetone and 12g. of recently fused potassium acetate and refluxed for 20 hours. Themixture was com centrated to a small volume under reduced pressure,diluted with water and the reaction product was extracted with ether;the extract was washed with water, dried over anhydrous sodium sulfateand the ether was evaporated. Recrystallization of the residue fromacetone-hexane afforded the 21-acetate of16a-methyl-allopregnane-17,2ldiol-3,11,20-trione.

A suspension of 3 g. of the above compound in 60 cc. of chloroformcontaining 0.6 cc. of ethanol was saturated with dry hydrogen chloridefor 1 minutes under strong stirring; there was then added under stirringand in the course of 50 minutes 150 cc. of chloroform containing 2.1molar equivalents of bromine, waiting until decolorization occurredbefore each addition. The mixture was stirred for 5 minutes further,diluted with 150 cc. of ether and the precipitate was collected byfiltration, thus giving the ZI-acetate of2,4-dibromo-allopregnan-170:,21- diol-3,l1,20-tri-one in crude form.

The above compound was dissolved in 20 cc. of dimethylacetamide andadded to a suspension of 1.5 g. of calcium carbonate in 30 cc. ofdimethylacetamide previously heated to boiling; the mixture was refluxedunder strong stirring for 15 minutes, cooled, poured into Water andacidified with hydrochloric acid. The precipitate was collected; washedwith water, dried and recrystallized from acetonehexane, thus furnishingthe 21-acetate of 16u-methyl-n -pregnadiene-17a,2l-diol 3,11,20-trione,identical with an authentic sample of the 21-acetate of16e-methyl-prednisone.

Example 18 A mixture of g. of A -pregnen-3e-ol-11,20-dione, 300 cc. ofanhydrous benzene, 120 cc. of ethylene glycol distilled over sodiumhydroxide and 1.6 g. of p-toluenesulfonic acid was refluxed for 12 hourswith the use of a water separator. Aqueous sodium bicarbonate solutionwas added to the cooled mixture, the organic layer was separated, washedwith water, dried over anhydrous sodium sulfate and the solvent wasevaporated. There was thus obtained the 20 cycloethyleneketal of Apregnen-3a-ol-11,20-dione, which was used for the next step withoutfurther purification. A small amount was purified by chromatography onneutral alumina.

The above compound was dissolved in 100 cc. of tetrahydrofurane andadded to a mixture of 3 g. of lithium aluminum hydride and 200 cc. ofanhydrous tetrahydrofurane, little by little, with stirring and cooling.The mixture was refluxed for 4 hours, cooled, treated dropwise withacetone to decompose the excess of hydride, then aqueous saturatedsodium sulfate solution was added, followed by anhydrous sodium sulfate;the solid was filtered and the solvent was evaporated from the filtrate.There was thus obtained 20-ethylenedioxy- A -pregnene-3u,11B-diol incrude form. This compound was dissolved in 200 cc. of acetone, treatedwith 1 g. of p-toluenesulfonic acid and a few cc. of Water and keptovernight at room temperature; it was then concentrated to a smallvolume under reduced pressure, diluted with water and the precipitatewas collected, washed with water, dried and recrystallized fromacetone-hexane, thus giving A -pregnene-3a,1 l 8diol-20-one.

2 g. of the above compound was dissolved in 50 cc. of an ether solutionof diazomethane prepared from 12.5 g. of nitrosomethylurea and themixture was kept for 24 hours at room temperature. 1.2 cc. of aceticacid was then added, the solution was evaporated to dryness underreduced pressure in a bath at a temperature below 40 C. and the residuewas recrystallized from acetone to produce the pyrazoline, which wasthen decomposed by the thermal treatment described by Wettstein in Helv.Chim. Acta, XXVII, 1803 (1944), by gradually heating to 180 C. in highvacuum. Recrystallization from acetone of the crude product afforded16-methyl-A -pregnene-3 oz, 1 1 fl-diol-ZO-one.

By treatment of the above compound with an excess of acetic anhydride inpyridine at room temperature, followed by the usual workup, there wasobtained the 3 acetate of 16 methyl A pregnene 341,115- diol 20 one.

In accordance with the reactions heretofore set forth there was prepared10 g. of the 3-acetate of 16-methyl- A -pregnene-3a,11,8-diol-20-one,which was dissolved with slight heating in 125 cc. ofdirnethylformamide; the mixture was cooled, treated with 4.2 cc. ofmesyl chloride and 5 cc. of pyridine and heated at C. for half an hour.Water was added to the cooled mixture, the product was extracted withethyl acetate, the extract was washed with water, dried over anhydroussodium sulfate and the solvent was evaporated. Recrystallization of theresidue from acetone-hexane yielded the acetate of 1S-methyl-A-pregnadien-3u-ol-20-one.

8 g. of the above compound was treated with a solution of 5 g. ofpotassium hydroxide in a mixture of cc. of acetone and 20 cc. of Water,heated on the steam bath for 1 hour, acidified with acetic acid,concentrated to a small volume under reduced pressure, diluted withwater and the precipitate was collected, thus giving the free16-methyl-A -pregnadien-3a-ol-ZO-one, which was used for the next stepwithout further purification.

The above crude compound was dissolved in 200 cc. of acetic acid andslowly treated under stirring with a solution of 2 g. of chromiumtrioxide in 40 cc. of 50% acetic acid, taking care that the temperatureremained below 15 C. It was then stirred at this temperature for 1 hourmore, poured into ice water and the precipitate was collected, washedwith water, dried and recrystaL lized from acetone-hexane, thusaffording 16-methyl- A -pregnadiene-3,20-dione.

A mixture of 7.5 g. of the above compound, 75 cc. of pure dioxane and 12cc. of 0.4 N perchloric acid was treated in the dark at room temperaturewith 4.2 g. of N-bromoacetamide which was added with stirring and in thecourse of 1 hour. The stirring was continued for 1 hour further and thesolution was then treated with 10% sodium sulfite solution until thestarch-potassium iodide indicator paper no longer turned blue; 500 g. ofice and 120 cc. of chloroform were added and the organic layer wasseparated, successively washed with sodium bicarbonate solution andwater, evaporated under reduced pressure in a bath at a temperaturebelow 25 C. and the residue was triturated with a little cold acetone.There was thus obtained 16-methyl9a-bromo-A pregnen-l1,B-ol-3,20-dione.

The above crude compound was dissolved in 20 cc. of dioxane and slowlyadded to a mixture of 3.2 g. of anhydrous potassium acetate and 40 cc.of absolute ethanol which had been heated nearly to boiling. The mixturewas refluxed for 45 minutes, cooled and treated with 50 cc. of ice waterunder continuous stirring. The precipitate was collected, washed withwater and dried, thus yielding 16methyl-9,B,1 1 fl-oxido-A-pregnene-3,20-dione.

The above crude product was dissolved in 150 cc. of methylene chloride,cooled to C. and the solution was treated with a mixture of 12 g. ofanhydrous hydrogen fluoride and 20 cc. of tetrahydrofurane previouslycooled in a Dry Ice-acetone bath; the hydrogen fluoride solution hadbeen placed in a polyethylene flask fitted with a magnetic stirrer. Theaddition was effected little by little, with stirring, over a period ofabout 20 minutes; the mixture was then stirred at -1 0 C. for 6 hoursmore, neutralized by the cautious addition of aqueous sodium bicarbonatesolution, the mixture was transferred to a separate funnel and theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated until abundant precipitation. After cooling theprecipitate was collected, redissolved in 40 cc. of hot ethyl acetate,filtered while hot from insoluble material and the filtrate was cooled,thus affording the crystalline 16-methyl-9a-fluoro-A -pregnen1 1 5-01-3,20- dione.

A solution of 5 g. of the above compound in 65 cc. of chloroform and 155cc. of methanol was cooled to 0 C. and treated under stirring with 10cc. of 35% hydrogen peroxide and simultaneously with a solution of 5 g.of sodium hydroxide in 50 cc. of water, drop wise and maintaining thetemperature around 0 C. The mixture was then stirred for one hour moreat 0 C., then at room temperature for 16 hours, poured into ice water,extracted with chloroform and the combined chloroform extracts werewashed with water, dried over anhydrous sodium sulfate and the solventwas evaporated. Recrystallization of the residue from acetone-hexanefurnished 16- methyl-9a fluOl'0-16oz,17oa oxido-pregnan 11B-ol-3,20-dione.

cc. of constant boiling aqueous hydrobromic acid solution was slowlyadded to a stirred solution of 5 g. of 16,8-methyl-9a-fluoro 16u,17aoxido-pregnan 11,6-01- 3,20-dione in 100 cc. of pure acetone,maintaining the temperature around 10 C.; the mixture was stirred for 1hour more at 10 C., diluted with ice water and the precipitate wascollected, and recrystallized from acetone-hexane. There was thusobtained 16-methy1-9afluoro-A -pregnene-115,17ot-di0l-3 ,20-dione.

By applying the hydrogenation method described in Example 1, the lattercompound was converted to 1600- methyl-9 u-fluoro-pregnane-l1B,17a-diol-3 ,20-dione.

Example 19 16 methyl-A -pregnadiene 3,20 dione was prepared as describedin Example 18 and then further converted to the 16-methyl-16a,17a-oxidoderivative, then to 16-methyl-A -pregnadien-l7a-ol-3,2O-dione, andfinally to 16a-methyl-A -pregnen-17a-ol-3,20-dione by the process stepsas described in Example 1.

We claim:

1. A process for producing a z-Il16'thYl-170t-hYdI'OXY-ZO-ketO-pregnane, comprising reacting a 16(3-methyl-16a,17u-oxido-ZO-keto-pregnane with a hydrogen halide in an inert organicsolvent selected from the group consisting of acetone, methyl-ethylketone and dioxane so as to obtain the corresponding 16-methyl-A-17a-hydroxy- ZO-keto-pregnane, and reacting the latter with hydrogen inthe presence of a hydrogenation catalyst selected from the groupconsisting of palladium and nickel so as to obtain the corresponding160L-m6thy1-170t-hYdI'OXY-20-k6t0- pregnane.

2. The process as described in claim 1, characterized in that thehydrogen halide is employed in the form of a tertiary amine hydrohalide.

3. A process for producing a 16a-methyl-17a-hydroxy- 20-keto-pregnane,as described in claim 1, characterized in that a16B-methyl-16a,17u-oxido-20-keto-pregnane is reacted with a hydrogenhalide selected from the group consisting of hydrogen chloride, hydrogenbromide and hydrogen iodide, in acetone, so as to obtain thecorresponding 16-methyl-A -17a-hydroxy-20-keto-pregnane.

4. In a process for producing a 16a-methyl-17a-hydroxy-20-keto-pregnane,the step of reacting a 16fl-methyl-l6a,17a-oxido-20-keto-pregnanederivative with aqueous hydrobromic acid in acetone solution at atemperature of from about 10 to room temperature so as to obtain thecorresponding 16-methyl-A -17a-hydroxy 20 ketopregnane.

5. In a process for producing a 16a-methyl-17u-hydroxy-ZO-keto-pregnane,the step of reacting a 16fi-methyl-1611,17a-oxido-20-keto-pregnane withthe hydrohalide of a tertiary amine in an alcoholic solvent at refluxtemperature so as to obtain the corresponding 16-methyl-A17a-hydroxy-20-keto-pregnane.

6. A process as described in claim 1, characterized in that the startingcompound is selected from the group consisting of the compounds of theformulas:

CHzR

wherein R is selected from the group consisting of hydrogen, hydroxy andacyloxy; X is selected from the group consisting of hydrogen andfluorine; Y is selected from the group consisting of =0, u-hydroxy,B-hydroxy, a-acyloxy and B-acyloxy; Y is selected from the groupconsisting of =0, u-hYdIOXY, B-hydroxy and a-acyloxy; when Y is =0, Z isselected from the group consisting of a single bond between C-5 and C-6with the hydrogen attached to C-5 in u-position and such single bondbetween C-5 and C-6 with the hydrogen attached to C-5 in B-position;when Y represents a member of the above described group other than =0, Zis selected from the group consisting of a double bond between C5 andC-6, a single bond between C5 and C-6 with the hydrogen at- 13 tached to(3-5 in a-position and a single bond between C-5 and -6 with thehydrogen attached to C in the fi-posititon; the aforesaid acyloxy andacyl groups being those of a hydrocarbon carboxylic acid having up to 12carbon atoms.

7. A process as described in claim 6, characterized in that the startingcompound is 16/3-methyl-16a,17a-oXido- A -pregnadien-3 ,8-ol-20-one andthat the end product is 16a-methyl-A -pregnadiene-Pafi,17a-diol-20-one.

8. A process as described in claim 6, characterized in that the startingcompound is 165-methyl-16a,17a-oxidoallopregnan-SB-ol-l1,20-dioneacetate and that the end product is lfizx-methyl-allopregnane3,8,17oc-dl0l 11,20- dione 3-acetate.

9. A process as described in claim 6, characterized in that the startingcompound is 16p3-methyl-16a,17a-oxido- A -pregnen-3 18-01-20-one acetateand that the end product is 16a-methyl-A -pregnene-3fi,l7u-diol-20-one3-acetate.

10. A process for producing a16-methyl-17a-hydroXy- ZO-keto pregnanecomprising reacting a A -20-ketopregnane with diazomethane followed bythermal decomposition of the intermediate pyrazoline formed, so as toobtain the corresponding 16-methyl-A -20-keto-pregnane, reacting thelatter derivative with alkaline hydrogen peroxide so as to obtain thecorresponding lfi-rnethyl- I6a,17a-oxido-20-keto-pregnane, reacting thelatter epoxide with a hydrogen halide in an inert organic solventselected from the group consisting of acetone, methylethyl ketone anddioxane so as to obtain the corresponding l6-methyl-A-17a-hydroxy-ZO-keto-pregnane, and reacting the latter with hydrogen inthe presence of a hydrogenation catalyst so as to obtain thecorresponding 16a-methyl-17a-hydroxy-20-keto-pregnane.

11. A compound of the formula wherein the hydrogen atom at C-5 isselected from the group consisting of the a-position and the,8-position.

12. A compound of the formula 13. A compound of the formula and O, and Zis a linkage between C4 and C5 selected from the group consisting of adouble and a saturated linkage with the hydrogen atom at 0-5 selectedfrom the group consisting of the a-hydrogen and the fi-hydrogen.

14. 16-methyl-A -pregnatriene 35,17ot-di0l-20- one.

15. The C-3 hydrocarbon carboxylic acid esters of up to 12 carbon atomsof 16-methyl-A -pregnatriene- 3 B,17a-diol-20-one.

16. 16-methyl-A -allopregnadiene 3,8,17zz diol- 20-one.

17. l6-methyl-A pregnadiene 3B,lla,17xtriOl-20 one.

18. 16-methyl-A -pregnadiene-3 ,8-17a-diol-20-one.

19. 16 methyl-A -pregnadiene 3B,17ocdi0l 11,20- dione.

20. 16-methyl-9a fluoro-A -pregnene-1113,17a-di0l-3, 20-dione.

21. 16-methyl-A -pregnadien-17a-ol-3,20-dione.

22. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and the acylradical of a hydrocarbon carboxylic acid of up to 12 carbon atoms.

References Cited by the Examiner UNITED STATES PATENTS 2,954,386 9/1960Beyler 260397.47 2,958,702 11/1960 Taub et a1 260397.45 2,984,678 5/1961Agnello et a1 260397.45 3,004,991 10/1961 Petrow 260397.4 3,053,8659/1962 Taub 260-397.45 3,122,573 2/1964 Nomine 260397.4

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, MORRIS LIEBMAN, IRVING MARCUS, Examiners.

22. A COMPOUND OF THE FORMULA: